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Drug targeting to the brain Jaap Rip1, Geert J Schenk1 and Albertus G de Boer*1,2 Address: 1BBB Research Group, Division of Pharmacology, LACDR, Univ. of Leiden, The Netherlands and 2Academic partner and Founder of toBBB technologies BV, Leiden, The Netherlands Email: Albertus G de Boer* -
[email protected] * Corresponding author
from Infectious diseases of the nervous system: pathogenesis and worldwide impact Paris, France. 10–13 September 2008 Published: 23 September 2008 BMC Proceedings 2008, 2(Suppl 1):S37
Infectious diseases of the nervous system: pathogenesis and worldwide impact
Roberto Bruzzone, Monique Dubois-Dalcq, Georges E Grau, Diane E Griffin and Krister Kristensson Meeting abstracts – A single PDF containing all abstracts in this Supplement is available
here.
This abstract is available from: http://www.biomedcentral.com/1753-6561/2/S1/S37 © 2008 Rip et al; licensee BioMed Central Ltd.
Many brain diseases (such as meningitis, encephalitis, multiple sclerosis (MS), stroke, brain tumors, epilepsy, Alzheimer's disease, AIDS related dementia, Parkinson's disease) are under treated or cannot be treated at all due to the presence of the barriers in the brain (blood-brain barrier, blood-cerebrospinal fluid barrier and the braincerebrospinal fluid barrier). The blood-brain barrier is facing the blood side and is the largest barrier for transport of macromolecular drugs from blood to brain. Therefore, targeting strategies to the BBB are necessary to selectively and specifically transport macromolecular drugs to the brain. This can be accomplished by exploiting receptormediated transport (RMT) systems at the blood-brain barrier. Moreover, enhanced selectivity can be obtained by targeting transport systems induced during disease conditions. Macromolecular protein drugs can be directly linked to a carrier molecule that fits to a RMT system. However, such applications often result in decreased activity of the resulting (fusion) protein and are prone to induce activation of and subsequent degradation by the immune system. Therefore, liposomal systems coated with carrier molecules are an alternative to deliver macromolecular protein drugs to the brain by targeting them to the blood-brain barrier.
blood-brain barrier endothelial cells to subsequently perform their therapeutic action in the brain. Genes can be attached to poly-cationic polymers like poly-ethyleneimines or incorporated into liposomal systems and targeted to the brain by a carrier molecule that fits to a RMT system. For this purpose we use a human applicable carrier protein known as CRM197. CRM197 is the non-toxic mutant of diphtheria toxin that uses the membrane-bound precursor of heparin-binding epidermal growth factor (HBEGF) as its transport receptor [1]. Membrane bound HBEGF is constitutively expressed on the blood-brain barrier Moreover, HB-EGF expression is strongly up-regulated on cerebral blood vessels in diseases with inflammatory events like Alzheimer's disease, Parkinson's disease, MS, stroke/ischemia, tumors, epilepsy and encephalitis. This may provide disease induced drug targeting to the brain. Research so far has shown in vitro proof of principle for the transport of biopharmaceuticals across the BBB [2-4]. Therefore, this brain drug delivery technology holds out a great promise for future therapeutic applications.
References 1.
A second, alternative approach may be to target genes to the brain. However, in our opinion it will be very difficult to transport such genes across the BBB. Our approach is to use the blood-brain barrier as a "protein factory" following delivery of genes encoding therapeutic proteins to the blood-brain barrier. Such proteins can be excreted by the
2. 3. 4.
Raab G, Klagsbrun M: Heparin-binding EGF-like growth factor. Biochim Biophys Acta 1997, 1333:F179-F199. Gaillard PJ, Visser CC, de Boer AG: Targeted delivery across the blood-brain barrier. Expert Opin Drug Deliv 2005, 2:299-309. Gaillard PJ, Brink A, De Boer AG: Diphtheria toxin receptor-targeted brain drug delivery. Int Congres Series 2005, 1277:185-195. de Boer AG, Gaillard PJ: Drug targeting to the brain. Annu Rev Pharmacol Toxicol 2007, 47:323-355.
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